Pyrazolylphenyl and pyrrolylphenyl inhibitors of LTA4H for treating inflammation

ABSTRACT

Two chemical genera of pyrazolylphenyl and pyrrolylphenyl derivatives are disclosed. They have the general formula: In these compounds ring (a) is a pyrazole or pyrrole; Q is selected from the group consisting of a direct bond, O, S, SO, SO2, NR1, CH2, CF2, and C(O); HET is a 4-7-membered saturated nitrogenous heterocycle; and taken together ZW is H or Z is (CH2)1-10 in which one or two (CH2) may optionally be replaced by —O—, —NR1—, —SO—, —S(O)2—, —C(═O)— or —C═O(NH)—; and W is hydrogen, acyl, hydroxyl, carboxyl, amino, carboxamido, aminoacyl, —COOalkyl, —CHO, heterocyclyl, substituted aryl or substituted heterocyclyl. The compounds are inhibitors of LTA4H (leukotriene A4 hydrolase). They are useful for the treatment and prevention and prophylaxis of inflammatory diseases and disorders.

RELATED APPLICATIONS

This application claims priority to U.S. Provisional Application No.60/821,474 filed Aug. 4, 2006, which is hereby incorporated herein byreference in its entirety.

FIELD OF THE INVENTION

The present invention relates to a chemical genus of pyrazolylphenyl andpyrrolylphenyl derivatives that are inhibitors of LTA4H (leukotriene A4hydrolase). They are useful for the treatment and prevention andprophylaxis of inflammatory diseases and disorders.

BACKGROUND OF THE INVENTION

The end products of the leukotriene pathway are potent inflammatorylipid mediators derived from arachidonic acid. They can potentiallycontribute to development of atherosclerosis and destabilization ofatherosclerotic plaques through lipid oxidation and/or proinflammatoryeffects. As described elsewhere, a gene on chromosome 13q12 has beenidentified as playing a major role in myocardial infarction (MI),[Helgadottir et al., Nature Genetics doi:10.1038/ng 1311, 8 Feb. 2004].This gene (ALOX5AP), herein after referred to as an MI disease gene,comprises nucleic acid that encodes 5-lipoxygenase activating protein(FLAP), herein after referred to as FLAP. DNA variants in the FLAP geneincrease risk for myocardial infarction by 1.8 fold and for stroke by1.7 fold. The leukotriene pathway, through FLAP, leads to the productionof leukotriene B4 by the enzyme leukotriene A4 hydrolase (LTA4H).Leukotriene B4 is one of the most potent chemokine mediators of arterialinflammation. Particular DNA variants in the gene encoding LTA4H alsoelevate risk for MI and stroke, as described elsewhere [Hakonarsson etal., J. Am. Med. Assoc. 293, 2245-2256 (2005)]. Individuals with a priorhistory of MI produce more leukotriene B4 when their isolatedneutrophils are stimulated with ionomycin. Increased LTB4 production isparticularly marked in male patients with a prior history of MI whocarry risk variants in the FLAP gene [Helgadottir et al.]. The treatment(prophylactic and/or therapeutic) of certain diseases and conditions(e.g., MI, acute coronary syndrome (ACS), stroke, atherosclerosis)associated with FLAP or with LTA4H can be accomplished by inhibitingLTA4H. Inhibiting LTA4H is advantageous for methods of treatment for MIor susceptibility to MI; for ACS (e.g., unstable angina,non-ST-elevation myocardial infarction (NSTEMI) or ST-elevationmyocardial infarction (STEMI)); for decreasing risk of a second MI; forstroke (including transient ischemic attack) or susceptibility tostroke; for atherosclerosis, such as for patients requiring treatment(e.g., angioplasty, stents, coronary artery bypass graft) to restoreblood flow in coronary arteries, such as patients requiring treatmentfor peripheral vascular disease including peripheral occlusive arterialdisease, critical limb ischemia (e.g., gangrene, ulceration), andintermittent claudication to restore blood flow in the lower limbs; foratherosclerotic reno-vascular disease; for abdominal aortic aneurysm;and/or for decreasing leukotriene synthesis (e.g., for treatment of MI).

US Patent Application Publication No. 20050043378 and 20050043379,relate to benzooxazol-2-yl, benzothiazol-2-yl and 1H-benzoimidazol-2-ylcompounds and derivatives thereof useful as leukotriene A4 hydrolase(LTA4H) inhibitors in treating inflammation and disorders associatedwith inflammation. These disclosures are incorporated herein byreference as they relate to utility.

SUMMARY OF THE INVENTION

In one aspect, the present invention relates to compounds exhibitingLTA4H enzyme inhibition, having general formula:

whereinring (a) is chosen from pyrazole and pyrrole, unsubstituted orsubstituted with from one to three substituents independently selectedfrom the group consisting of halogen, hydroxyl, loweralkyl, loweracyl,loweralkoxy, fluoroloweralkyl, fluoroloweralkoxy, formyl, cyano, nitro,phenyl and heteroaryl;Q is selected from the group consisting of a direct bond, O, S, SO, SO₂,NR¹, CH₂, CF₂, and C(O);n is zero or an integer from 1-4;p is an integer from 1-4;HET is a 4-7-membered saturated nitrogenous heterocycle; andtaken together ZW is H orZ is (CH₂)₁₋₁₀ in which one or two (CH₂) may optionally be replaced by—O—, —NR¹—, —SO—, —S(O)₂—, —C(═O)— or —C═O(NH)—;R¹ is chosen from H and lower alkyl; andW is selected from the group consisting of hydrogen, acyl, hydroxyl,carboxyl, amino, carboxamido, aminoacyl, —COOalkyl, —CHO, heterocyclyl,substituted aryl, substituted heterocyclyl, sulfonamide,—C(O)fluoroalkyl, —C(O)CH₂C(O)Oalkyl, —C(O)CH₂C(O)Ofluoroalkyl, —SH,—C(O)NH(OH), —C(O)N(OH)R⁴, —N(OH)C(O)OH, —N(OH)C(O)R⁴; andR⁴ is selected from the group consisting of H and lower alkyl.

A second aspect of the present invention relates to pharmaceuticalcompositions comprising a pharmaceutically acceptable carrier and atherapeutically effective amount of at least one compound of the generalformula described above.

A third aspect of the present invention relates to a method forinhibiting leukotriene A4 hydrolase comprising contacting the LTA4Henzyme with a therapeutically effective amount of a compound describedabove.

A fourth aspect of the present invention relates to a method fortreating a disorder associated with leukotriene A4 hydrolase comprisingadministering to a mammal a therapeutically effective amount of thecompound described above or a salt, hydrate or ester thereof.

DETAILED DESCRIPTION OF THE INVENTION

Throughout this specification the substituents are defined whenintroduced and retain their definitions.

In one aspect the invention relates to pyrazolylphenyl andpyrrolylphenyl derivatives useful as LTA4H enzyme inhibitors, having thegeneral formula:

The two parent genera conveniently break down into pyrazoles:

in which R² is H, halogen, hydroxyl, loweralkyl, loweracyl, loweralkoxy,fluoroloweralkyl, fluoroloweralkoxy, formyl, cyano, nitro, phenyl, orheteroaryl and pyrroles:

in which R³ is H, halogen, loweralkyl, loweracyl, loweralkoxy,fluoroloweralkyl, fluoroloweralkoxy, formyl, cyano, phenyl, heteroarylor nitro. In certain embodiments, Q is —O—. In many embodiments, n is 1,2 or 3; and p is 2 or 3. In certain embodiments, HET is piperidine orpyrrolidine, particularly 1-piperidine and 2-pyrrolidine, and ZW ishydrogen, or Z is (CH₂)₁₋₁₀; in which one or two (CH₂) may optionally bereplaced by —O— —NR¹—, —SO—, —S(O)₂—, —C(═O)— or —C═O(NH), and W isselected from the group consisting of acyl, hydroxy, carboxy, amino,carboxamido and aminoacyl. Z may be, for example, (CH₂)₁₋₃ or —C(O)—,and W may be hydrogen, acyl, hydroxyl, amino, carboxamido, aminoacyl,COOloweralkyl or COOH. R² is often H, loweralkyl, trifluoromethyl orhalogen. R³ is often H, halogen, loweralkyl, loweracyl, loweralkoxy,fluoroloweralkyl, fluoroloweralkoxy, formyl, cyano, phenyl, heteroarylor nitro.

The present invention provides a method for inhibiting leukotriene A4hydrolase comprising contacting the LTA4H enzyme with a therapeuticallyeffective amount of a compound according to the general formula

It may be found upon examination that additional species and genera notpresently excluded are not patentable to the inventors in thisapplication. In such a case, the exclusion of species and genera inapplicants' claims are to be considered artifacts of patent prosecutionand not reflective of the inventors' concept or description of theirinvention. The invention, in a composition aspect, is all compounds ofthe general formula above, except those that are in the public'spossession. The invention, in a method aspect, is a method employingcompounds of the general formula above, except those methods that are inthe public's possession.

The present invention provides a method for treating a disorderassociated with leukotriene A4 hydrolase comprising administering to amammal a therapeutically effective amount of a compound or a salt,hydrate or ester thereof according to the general formula given above.In some embodiments the disorder is associated with inflammation. Insome embodiments the disorder is selected from allergic inflammation,acute inflammation and chronic inflammation.

Compounds of the genus represented by the general formula above areinhibitors of LTA4H enzyme. As such they have utility in treating andpreventing inflammatory diseases and disorders, as described above,particularly for such conditions as asthma, chronic obstructed pulmonarydisease (COPD), atherosclerosis, rheumatoid arthritis, multiplesclerosis, inflammatory bowel diseases (IBD; including Crohn's diseaseand ulcerative colitis), or psoriasis, which are each characterized byexcessive or prolonged inflammation at some stage of the disease.

Recent research indicates that the compounds are also useful fortreating and preventing atherosclerosis, thrombosis, stroke, acutecoronary syndrome, stable angina, peripheral vascular disease, criticalleg ischemia, intermittent claudication, abdominal aortic aneurysm andmyocardial infarction atherosclerosis, thrombosis, stroke, acutecoronary syndrome and myocardial infarct.

The compounds may be presented as salts. The term “pharmaceuticallyacceptable salt” refers to salts whose counter ion derives frompharmaceutically acceptable non-toxic acids and bases. Suitablepharmaceutically acceptable base addition salts for the compounds of thepresent invention include, but are not limited to, metallic salts madefrom aluminum, calcium, lithium, magnesium, potassium, sodium and zincor organic salts made from lysine, N,N-dialkyl amino acid derivatives(e.g. N,N-dimethylglycine, piperidine-1-acetic acid andmorpholine-4-acetic acid), N,N′-dibenzylethylenediamine, chloroprocaine,choline, diethanolamine, ethylenediamine, meglumine (N-methylglucamine)and procaine. When the compounds contain a basic residue, suitablepharmaceutically acceptable base addition salts for the compounds of thepresent invention include inorganic acids and organic acids. Examplesinclude acetate, benzenesulfonate (besylate), benzoate, bicarbonate,bisulfate, carbonate, camphorsulfonate, citrate, ethanesulfonate,fumarate, gluconate, glutamate, bromide, chloride, isethionate, lactate,maleate, malate, mandelate, methanesulfonate, mucate, nitrate, pamoate,pantothenate, phosphate, succinate, sulfate, tartrate,p-toluenesulfonate, and the like.

For convenience and clarity certain terms employed in the specification,examples and claims are described herein.

Alkyl is intended to include linear, branched, or cyclic hydrocarbonstructures and combinations thereof. Lower alkyl refers to alkyl groupsof from 1 to 6 carbon atoms. Examples of lower alkyl groups includemethyl, ethyl, propyl, isopropyl, butyl, s- and t-butyl and the like.Preferred alkyl groups are those of C₂₀ or below. Cycloalkyl is a subsetof alkyl and includes cyclic hydrocarbon groups of from 3 to 8 carbonatoms. Examples of cycloalkyl groups include c-propyl, c-butyl,c-pentyl, norbornyl and the like.

C₁ to C₂₀ hydrocarbon includes alkyl, cycloalkyl, alkenyl, alkynyl,aryl, arylalkyl and combinations thereof. Examples include phenethyl,cyclohexylmethyl, camphoryl, adamantyl and naphthylethyl.

Alkoxy or alkoxyl refers to groups of from 1 to 8 carbon atoms of astraight, branched, cyclic configuration and combinations thereofattached to the parent structure through oxygen. Examples includemethoxy, ethoxy, propoxy, isopropoxy, cyclopropyloxy, cyclohexyloxy andthe like. Lower-alkoxy refers to groups containing one to four carbons.

Alkoxyalkyl refers to ether groups of from 3 to 8 atoms of a straight,branched, cyclic configuration and combinations thereof attached to theparent structure through an alkyl. Examples include methoxymethyl,methoxyethyl, ethoxypropyl, and the like.

Alkoxyaryl refers to alkoxy substituents attached to an aryl, whereinthe aryl is attached to the parent structure. Arylalkoxy refers to arylsubstituents attached to an oxygen, wherein the oxygen is attached tothe parent structure. Substituted arylalkoxy refers to a substitutedaryl substituent attached to an oxygen, wherein the oxygen is attachedto the parent structure.

Acyl refers to groups of from 1 to 8 carbon atoms of a straight,branched, cyclic configuration, saturated, unsaturated and aromatic andcombinations thereof, attached to the parent structure through acarbonyl functionality. One or more carbons in the acyl residue may bereplaced by nitrogen, oxygen or sulfur as long as the point ofattachment to the parent remains at the carbonyl. Examples includeacetyl, benzoyl, propionyl, isobutyryl, t-butoxycarbonyl,benzyloxycarbonyl and the like. Lower-acyl refers to groups containingone to four carbons.

Aryl and heteroaryl mean a 5- or 6-membered aromatic or heteroaromaticring containing 0-3 heteroatoms selected from O, N, or S; a bicyclic 9-or 10-membered aromatic or heteroaromatic ring system containing 0-3heteroatoms selected from O, N, or S; or a tricyclic 13- or 14-memberedaromatic or heteroaromatic ring system containing 0-3 heteroatomsselected from O, N, or S. The aromatic 6- to 14-membered carbocyclicrings include, e.g., benzene and naphthalene, and according to theinvention benzoxalane and residues in which one or more rings arearomatic, but not all need be. The 5- to 10-membered aromaticheterocyclic rings include, e.g., imidazole, pyridine, indole,thiophene, benzopyranone, thiazole, furan, benzimidazole, quinoline,isoquinoline, quinoxaline, pyrimidine, pyrazine, tetrazole and pyrazole.

Arylalkyl refers to a substituent in which an aryl residue is attachedto the parent structure through alkyl. Examples are benzyl, phenethyland the like. Heteroarylalkyl refers to a substituent in which aheteroaryl residue is attached to the parent structure through alkyl.Examples include, e.g., pyridinylmethyl, pyrimidinylethyl and the like.Heterocyclylalkyl refers to a substituent in which a heterocyclylresidue is attached to the parent structure through alkyl. Examplesinclude morpholinoethyl and pyrrolidinylmethyl.

Heterocycle means a cycloalkyl or aryl residue in which from one tothree carbons is replaced by a heteroatom selected from the groupconsisting of N, O and S. The nitrogen and sulfur heteroatoms mayoptionally be oxidized, and the nitrogen heteroatom may optionally bequaternized. Examples of heterocycles include pyrrolidine, pyrazole,pyrrole, indole, quinoline, isoquinoline, tetrahydroisoquinoline,benzofuran, benzodioxan, benzodioxole (commonly referred to asmethylenedioxyphenyl, when occurring as a substituent), tetrazole,morpholine, thiazole, pyridine, pyridazine, pyrimidine, thiophene,furan, oxazole, oxazoline, isoxazole, dioxane, tetrahydrofuran and thelike. It is to be noted that heteroaryl is a subset of heterocycle inwhich the heterocycle is aromatic. Examples of heterocyclyl residuesadditionally include piperazinyl, 2-oxopiperazinyl, 2-oxopiperidinyl,2-oxo-pyrrolidinyl, 2-oxoazepinyl, azepinyl, 4-piperidinyl,pyrazolidinyl, imidazolyl, imidazolinyl, imidazolidinyl, pyrazinyl,oxazolidinyl, isoxazolidinyl, thiazolidinyl, isothiazolyl,quinuclidinyl, isothiazolidinyl, benzimidazolyl, thiadiazolyl,benzopyranyl, benzothiazolyl, tetrahydrofuryl, tetrahydropyranyl,thienyl, benzothienyl, thiamorpholinyl, thiamorpholinylsulfoxide,thiamorpholinylsulfone, oxadiazolyl, triazolyl and tetrahydroquinolinyl.

An oxygen heterocycle is a heterocycle containing at least one oxygen inthe ring; it may contain additional oxygens, as well as otherheteroatoms. A sulphur heterocycle is a heterocycle containing at leastone sulphur in the ring; it may contain additional sulphurs, as well asother heteroatoms. A nitrogen heterocycle is a heterocycle containing atleast one nitrogen in the ring; it may contain additional nitrogens, aswell as other heteroatoms. Oxygen heteroaryl is a subset of oxygenheterocycle; examples include furan and oxazole. Sulphur heteroaryl is asubset of sulphur heterocycle; examples include thiophene and thiazine.Nitrogen heteroaryl is a subset of nitrogen heterocycle; examplesinclude pyrrole, pyridine and pyrazine. A saturated nitrogenousheterocycle is a subset of nitrogen heterocycle. Saturated nitrogenousheterocycle contain at least one nitrogen and may contain additionalnitrogens, as well as other heteroatoms. Examples include pyrrolidine,pyrazolidine, piperidine, morpholine, and thiomorpholine.

Substituted alkyl, aryl, cycloalkyl, heterocyclyl etc. refer to alkyl,aryl, cycloalkyl, or heterocyclyl wherein up to three H atoms in eachresidue are replaced with halogen, haloalkyl, hydroxy, loweralkoxy,carboxy, carboalkoxy (also referred to as alkoxycarbonyl), carboxamido(also referred to as alkylaminocarbonyl), cyano, carbonyl, nitro, amino,alkylamino, dialkylamino, mercapto, alkylthio, sulfoxide, sulfone,acylamino, amidino, phenyl, benzyl, heteroaryl, phenoxy, benzyloxy, orheteroaryloxy.

The terms “halogen” and “halo” refer to fluorine, chlorine, bromine oriodine.

The term “prodrug” refers to a compound that is made more active invivo.

Activation in vivo may come about by chemical action or through theintermediacy of enzymes. Microflora in the GI tract may also contributeto activation in vivo.

It will be recognized that the compounds of this invention can exist inradiolabeled form, i.e., the compounds may contain one or more atomscontaining an atomic mass or mass number different from the atomic massor mass number usually found in nature. Radioisotopes of hydrogen,carbon, phosphorous, fluorine, and chlorine include ²H, ³H, ¹³C, ¹⁴C,¹⁵N, ³⁵S, ¹⁸F, and ³⁶Cl, respectively. Compounds that contain thoseradioisotopes and/or other radioisotopes of other atoms are within thescope of this invention. Tritiated, i.e. ³H, and carbon-14, i.e., ¹⁴C,radioisotopes are particularly preferred for their ease in preparationand detectability. Radiolabeled compounds of the present invention andprodrugs thereof can generally be prepared by methods well known tothose skilled in the art. Conveniently, such radiolabeled compounds canbe prepared by carrying out the procedures disclosed in the Examples andSchemes by substituting a readily available radiolabeled reagent for anon-radiolabeled reagent.

As used herein, and as would be understood by the person of skill in theart, the recitation of “a compound” is intended to include salts,solvates, co-crystals and inclusion complexes of that compound.

The term “solvate” refers to a compound of formula I in the solid state,wherein molecules of a suitable solvent are incorporated in the crystallattice. A suitable solvent for therapeutic administration isphysiologically tolerable at the dosage administered. Examples ofsuitable solvents for therapeutic administration are ethanol and water.When water is the solvent, the solvate is referred to as a hydrate. Ingeneral, solvates are formed by dissolving the compound in theappropriate solvent and isolating the solvate by cooling or using anantisolvent. The solvate is typically dried or azeotroped under ambientconditions. Co-crystals are combinations of two or more distinctmolecules arranged to create a unique crystal form whose physicalproperties are different from those of its pure constituents.Pharmaceutical co-crystals have recently become of considerable interestfor improving the solubility, formulation and bioavailability of suchdrugs as itraconazole [see Remenar et al. J. Am. Chem. Soc. 125,8456-8457 (2003)] and fluoxetine. Inclusion complexes are described inRemington: The Science and Practice of Pharmacy 19^(th) Ed. (1995)volume 1, page 176-177. The most commonly employed inclusion complexesare those with cyclodextrins, and all cyclodextrin complexes, naturaland synthetic, with or without added additives and polymer(s), asdescribed in U.S. Pat. Nos. 5,324,718 and 5,472,954, are specificallyencompassed within the claims. The disclosures of Remington and the '718and '954 patents are incorporated herein by reference.

The compounds described herein may contain asymmetric centers and maythus give rise to enantiomers, diastereomers, and other stereoisomericforms. Each chiral center may be defined, in terms of absolutestereochemistry, as (R)- or (S)-. The present invention is meant toinclude all such possible isomers, as well as, their racemic andoptically pure forms. Optically active (R)- and (S)-isomers may beprepared using chiral synthons or chiral reagents, or resolved usingconventional techniques. The prefix “rac” refers to a racemate. When thecompounds described herein contain olefinic double bonds or othercenters of geometric asymmetry, and unless specified otherwise, it isintended that the compounds include both E and Z geometric isomers. Therepresentation of the configuration of any carbon-carbon double bondappearing herein is selected for convenience only, and unless explicitlystated, is not intended to designate a particular configuration. Thus acarbon-carbon double bond depicted arbitrarily as E may be Z, E, or amixture of the two in any proportion. Likewise, all tautomeric forms arealso intended to be included.

The graphic representations of racemic, ambiscalemic and scalemic orenantiomerically pure compounds used herein are taken from Maehr, J.Chem. Ed. 62, 114-120 (1985): solid and broken wedges are used to denotethe absolute configuration of a chiral element; wavy lines and singlethin lines indicate disavowal of any stereochemical implication whichthe bond it represents could generate; solid and broken bold lines aregeometric descriptors indicating the relative configuration shown butdenoting racemic character; and wedge outlines and dotted or brokenlines denote enantiomerically pure compounds of indeterminate absoluteconfiguration.

Terminology related to “protecting”, “deprotecting” and “protected”functionalities occurs throughout this application. Such terminology iswell understood by persons of skill in the art and is used in thecontext of processes that involve sequential treatment with a series ofreagents. In that context, a protecting group refers to a group, whichis used to mask a functionality during a process step in which it wouldotherwise react, but in which reaction is undesirable. The protectinggroup prevents reaction at that step, but may be subsequently removed toexpose the original functionality. The removal or “deprotection” occursafter the completion of the reaction or reactions in which thefunctionality would interfere. Thus, when a sequence of reagents isspecified, as it is in the processes of the invention, the person ofordinary skill can readily envision those groups that would be suitableas “protecting groups”. Suitable groups for that purpose are discussedin standard textbooks in the field of chemistry, such as ProtectiveGroups in Organic Synthesis by T. W. Greene [John Wiley & Sons, NewYork, 1991], which is incorporated herein by reference.

A comprehensive list of abbreviations utilized by organic chemistsappears in the first issue of each volume of the Journal of OrganicChemistry. The list, which is typically presented in a table entitled“Standard List of Abbreviations”, is incorporated herein by reference.

LTA4H inhibitors have been shown to be effective anti-inflammatoryagents in pre-clinical studies. For example, oral administration ofLTA4H inhibitor SC57461 to rodents resulted in the inhibition ofionophore-induced LTB4 production in mouse blood ex vivo, and in ratperitoneum in vivo (Kachur et al., 2002, J. Pharm. Exp. Ther. 300(2),583-587). Furthermore, eight weeks of treatment with the same inhibitorcompound significantly improved colitis symptoms in a primate model(Penning, 2001, Curr. Pharm. Des. 7(3): 163-179). The spontaneouscolitis that develops in these animals is very similar to human IBD.Therefore persons of skill in the art accept that positive results inLTA4H models are predictive of therapeutic utility in this and otherhuman inflammatory diseases.

The inflammatory response is characterized by pain, increasedtemperature, redness, swelling, or reduced function, or by a combinationof two or more of these symptoms. The terms inflammation, inflammatorydiseases or inflammation-mediated diseases or conditions include, butare not limited to, acute inflammation, allergic inflammation, andchronic inflammation.

Autoimmune diseases are associated with chronic inflammation. There areabout 75 different autoimmune disorders known that may be classifiedinto two types, organ-specific (directed mainly at one organ) andnon-organ-specific (affecting multiple organs).

Examples of organ-specific autoimmune disorders are insulin-dependentdiabetes (Type I) which affects the pancreas, Hashimoto's thyroiditisand Graves' disease which affect the thyroid gland, pernicious anemiawhich affects the stomach, Cushing's disease and Addison's disease whichaffect the adrenal glands, chronic active hepatitis which affects theliver; polycystic ovary syndrome (PCOS), celiac disease, psoriasis,inflammatory bowel disease (IBD) and ankylosing spondylitis.

Examples of non-organ-specific autoimmune disorders are rheumatoidarthritis, multiple sclerosis, systemic lupus and myasthenia gravis.

Furthermore, the compounds, compositions and methods of the presentinvention are useful in treating cancer. Leukotriene synthesis has beenshown to be associated with different types of cancer includingesophageal cancer, brain cancer, pancreatic cancer, colon cancer.

The terms “methods of treating or preventing” mean amelioration,prevention or relief from the symptoms and/or effects associated withlipid disorders. The term “preventing” as used herein refers toadministering a medicament beforehand to forestall or obtund an acuteepisode. The person of ordinary skill in the medical art (to which thepresent method claims are directed) recognizes that the term “prevent”is not an absolute term. In the medical art it is understood to refer tothe prophylactic administration of a drug to substantially diminish thelikelihood or seriousness of a condition, and this is the sense intendedin applicants' claims. As used herein, reference to “treatment” of apatient is intended to include prophylaxis. Throughout this application,various references are referred to. The disclosures of thesepublications in their entireties are hereby incorporated by reference asif written herein.

The term “mammal” is used in its dictionary sense. Humans are includedin the group of mammals, and humans would be the preferred subjects ofthe methods of.

While it may be possible for the compounds of the present invention tobe administered as the raw chemical, it is preferable to present them asa pharmaceutical composition. According to a further aspect, the presentinvention provides a pharmaceutical composition comprising at least onecompound described supra, or a pharmaceutically acceptable salt orsolvate thereof, together with one or more pharmaceutically carriersthereof and optionally one or more other therapeutic ingredients. Thecarrier(s) must be “acceptable” in the sense of being compatible withthe other ingredients of the formulation and not deleterious to therecipient thereof.

The formulations include those suitable for oral, parenteral (includingsubcutaneous, intradermal, intramuscular, intravenous andintraarticular), rectal and topical (including dermal, buccal,sublingual and intraocular) administration. The most suitable route maydepend upon the condition and disorder of the recipient. Theformulations may conveniently be presented in unit dosage form and maybe prepared by any of the methods well known in the art of pharmacy. Allmethods include the step of bringing into association at least onecompound of the present invention or a pharmaceutically acceptable saltor solvate thereof (“active ingredient”) with the carrier, whichconstitutes one or more accessory ingredients. In general, theformulations are prepared by uniformly and intimately bringing intoassociation the active ingredient with liquid carriers or finely dividedsolid carriers or both and then, if necessary, shaping the product intothe desired formulation.

Formulations of the present invention suitable for oral administrationmay be presented as discrete units such as capsules, cachets or tabletseach containing a predetermined amount of the active ingredient; as apowder (including micronized and nanoparticulate powders) or granules;as a solution or a suspension in an aqueous liquid or a non-aqueousliquid; or as an oil-in-water liquid emulsion or a water-in-oil liquidemulsion. The active ingredient may also be presented as a bolus,electuary or paste.

A tablet may be made by compression or molding, optionally with one ormore accessory ingredients. Compressed tablets may be prepared bycompressing in a suitable machine the active ingredient in afree-flowing form such as a powder or granules, optionally mixed with abinder, lubricant, inert diluent, lubricating, surface active ordispersing agent. Molded tablets may be made by molding in a suitablemachine a mixture of the powdered compound moistened with an inertliquid diluent. The tablets may optionally be coated or scored and maybe formulated so as to provide sustained, delayed or controlled releaseof the active ingredient therein.

The pharmaceutical compositions may include a “pharmaceuticallyacceptable inert carrier”, and this expression is intended to includeone or more inert excipients, which include starches, polyols,granulating agents, microcrystalline cellulose, diluents, lubricants,binders, disintegrating agents, and the like. If desired, tablet dosagesof the disclosed compositions may be coated by standard aqueous ornonaqueous techniques, “Pharmaceutically acceptable carrier” alsoencompasses controlled release means.

Compositions of the present invention may also optionally include othertherapeutic ingredients, anti-caking agents, preservatives, sweeteningagents, colorants, flavors, desiccants, plasticizers, dyes, and thelike. Any such optional ingredient must, of course, be compatible withthe compound of the invention to insure the stability of theformulation. The dose range for adult humans is generally from 0.1 μg to10 g/day orally. Tablets or other forms of presentation provided indiscrete units may conveniently contain an amount of compound of theinvention which is effective at such dosage or as a multiple of thesame, for instance, units containing 0.1 mg to 500 mg, usually around 5mg to 200 mg. The precise amount of compound administered to a patientwill be the responsibility of the attendant physician. However, the doseemployed will depend on a number of factors, including the age and sexof the patient, the precise disorder being treated, and its severity.The frequency of administration will depend on the pharmacodynamics ofthe individual compound and the formulation of the dosage form, whichmay be optimized by methods well known in the art (e.g. controlled orextended release tablets, enteric coating etc.).

Combination therapy can be achieved by administering two or more agents,each of which is formulated and administered separately, or byadministering two or more agents in a single formulation. Othercombinations are also encompassed by combination therapy. For example,two agents can be formulated together and administered in conjunctionwith a separate formulation containing a third agent. While the two ormore agents in the combination therapy can be administeredsimultaneously, they need not be. For example, administration of a firstagent (or combination of agents) can precede administration of a secondagent (or combination of agents) by minutes, hours, days, or weeks.Thus, the two or more agents can be administered within minutes of eachother or within any number of hours of each other or within any numberor days or weeks of each other. In some cases even longer intervals arepossible.

While in many cases it is desirable that the two or more agents used ina combination therapy be present in within the patient's body at thesame time, this need not be so. Combination therapy can also include twoor more administrations of one or more of the agents used in thecombination. For example, if agent X and agent Y are used in acombination, one could administer them sequentially in any combinationone or more times, e.g., in the order X-Y-X, X-X-Y, Y-X-Y, Y-Y-X,X-X-Y-Y, etc.

As LTA4H inhibitors, the compounds of formula T have utility in treatingand preventing inter alia inflammation. The compounds and compositionscan be used advantageously in combination with other agents useful intreating and preventing inflammatory conditions and for treating andpreventing atherosclerosis, thrombosis, stroke, acute coronary syndrome,stable angina, peripheral vascular disease, critical leg ischemia,intermittent claudication, abdominal aortic aneurysm and myocardialinfarction.

In general, the compounds of the present invention may be prepared bythe methods illustrated in the general reaction schemes as, for example,described below, or by modifications thereof, using readily availablestarting materials, reagents and conventional synthesis procedures. Inthese reactions, it is also possible to make use of variants that are inthemselves known, but are not mentioned here. The starting materials areeither commercially available, synthesized as described in the examplesor may be obtained by the methods well known to persons of skill in theart. The following specific non-limiting examples are illustrative ofthe invention.

General Procedure A: Alkylation of pyrazole with boronic acid. A mixtureof 4-methoxyphenylboronic acid (2 mmol), pyrazoles (1 mmol),triethylamine (2 mmol), and Cu(OAc)₂ (1 mmol) in CH₂Cl₂ (2 mmol/10 mL)was stirred at room temperature for 3 h or until the reaction completed.After the reaction mixture was diluted with water and filtered through apad of Celite, the filtrate was extracted with ethyl acetate, washedbrine, and dried over Na₂SO₄. After concentrated in vacuo, the residuewas purified by a column chromatography on silica gel eluting withCH₂Cl₂ to the title compound.

General Procedure B: De-methoxylation with boron tribromide. To asolution of methoxide (2 mmol) in CH₂Cl₂ (7 mL) was added borontribromide (6 mmol) at −78° C. over 5 min. The reaction mixture wasstirred at −78° C. for 1 h, and then at room temperature for 18 h. Thereaction was quenched with sat. NaHCO₃ at 0° C., extracted with CH₂Cl₂,washed brine, and dried over Na₂SO₄. After concentrated in vacuo, thetitle compound was obtained, which was used to the next step withoutfurther purifications.

Procedure C: Alkylation of phenol. A mixture of the phenol (1 mmol),1-(2-chloroethyl)piperidine hydrochloride (2 mmol), K₂CO₃ (2.5 mmol), inDMF (1 mL) was stirred at 90° C. for 18 h. After the reaction mixturewas quenched with water, the reaction mixture was extracted with CH₂Cl₂,washed 10% NaOH, and brine, dried over Na₂SO₄. After concentrated invacuo, the residue was purified by a column chromatography on silica geleluting with 20% ethyl acetate/hexane to yield the title compound.

Example 1

Step 1

1-(4-Methoxy-phenyl)-1H-pyrazole: The title compound was prepared from4-methoxyphenylboronic acid (0.45 g, 2.94 mmol), pyrazole (0.4 g, 1.47mmol) using the general procedure A with a yield of 40% (0.4 g); MS(APCI) m/z: 203 (M+1, 100).

Step 2

4-Pyrazol-1-yl-phenol: The title compound was prepared from a solutionof 1-(4-methoxy-phenyl)-1H-pyrazole (0.33 g, 1.89 mmol) using thegeneral procedure B with a yield of 66% (0.2 g).

Step 3

1-[2-(4-Pyrazol-1-yl-phenoxy)-ethyl]-piperidine: The title compound wasprepared from 4-Pyrazol-1-yl-phenol (0.1 g, 0.62 mmol) and1-(2-chloroethyl)piperidine hydrochloride (0.23 g, 1.25 mmol) using thegeneral procedure C with a yield of 47% (80 mg); ¹H NMR (400 MHz, CDCl3)7.82 (dd, J=2.4, 0.4 Hz, 1H), 7.69 (br, dd, J=1.6, 0.4 Hz, 1H), 7.57 (d,J=9.2 Hz, 2H), 6.97 (d, J=9.2 Hz, 2H), 6.43 (dd, J=2.4, 2 Hz, 1H), 4.14(t, J=12, 6 Hz, 2H), 2.79 (t, J=12, 6 Hz, 2H), 2.52 (br, 4H), 1.61-1.47(m, 6H);

LC/MS (ESI): 97%.

Example 2

Step 1

1-(4-Methoxy-phenyl)-3-methyl-1H-pyrazole: The title compound wasprepared from 4-methoxyphenylboronic acid (1.85 g, 12.1 mmol),3-methyl-1H-pyrazoles (0.5 g, 6.1 mmol) using the general procedure Awith a yield of 30% (0.4 g); MS (APCI) m/z: 189 (M+1, 100).

Step 2

4-(3-Methyl-pyrazol-1-yl)-phenol: The title compound was prepared from1-(4-methoxy-phenyl)-3-methyl-1H-pyrazole (0.34 g, 1.86 mmol) using thegeneral procedure B with a yield of 47% (0.15 g).

Step 3

1-{2-[4-(3-Methyl-pyrazol-1-yl)-phenoxy]-ethyl}-piperidine: The titlecompound was prepared from 4-(3-methyl-pyrazol-1-yl)-phenol (0.1 g, 0.61mmol) and 1-(2-chloroethyl)piperidine hydrochloride (0.23 g, 1.25 mmol)using the general procedure C with a yield of 54% (90 mg); ¹H NMR (400MHz, CDCl3) 7.70 (d, J=2 Hz, 1H), 7.52 (d, J=9.2 Hz, 2H), 6.96 (d, J=9.2Hz, 2H), 6.20 (d, J=2 Hz, 1H), 4.12 (t, J=12, 6 Hz, 2H), 2.78 (t, J=12,6 Hz, 2H), 2.52 (br, 4H), 2.37 (s, 3H), 1.61-1.47 (m, 6H); LC/MS (ESI):97%.

Example 3

Step 1

1-(4-Methoxy-phenyl)-3,5-dimethyl-1-H-pyrazole: The title compound wasprepared from 4-methoxyphenylboronic acid (1.58 g, 10.4 mmol),3,5-dimethyl-1H-pyrazoles (0.5 g, 5.2 mmol) using the general procedureA with a yield of 90% (0.9 g); MS (APCI) m/z: 203 (M+1, 100).

Step 2

4-(3,5-Dimethyl-pyrazol-1-yl)-phenol: The title compound was preparedfrom 1-(4-methoxy-phenyl)-3,5-dimethyl-1-H-pyrazole (0.55 g, 2.72 mmol)using the general procedure B with a yield of 55% (0.28 g).

Step 3

1-{2-[4-(3,5-Dimethyl-pyrazol-1-yl)-phenoxy]-ethyl}-piperidine: Thetitle compound was prepared from 4-(3,5-dimethyl-pyrazol-1-yl)-phenol(0.1 g, 0.53 mmol), 1-(2-chloroethyl)piperidine hydrochloride (0.2 g,1.1 mmol) using the general procedure C with a yield of 44% (70 mg); ¹HNMR (400 MHz, CDCl3) 7.30 (d, J=8.8 Hz, 2H), 6.95 (d, J=8.8 Hz, 2H),5.96 (s, 1H), 4.14 (t, J=12, 6 Hz, 2H), 2.78 (t, J=12, 6 Hz, 2H), 2.53(br, 4H), 2.28 (s, 3H), 2.24 (s, 3H), 1.61-1.47 (m, 6H); LC/MS (ESI):96%.

Example 4

Step 1

1-(4-Methoxy-phenyl)-4-trifluoromethyl-1H-pyrazole: The title compoundwas prepared from 4-methoxyphenylboronic acid 1 (1.12 g, 7.34 mmol),5-trifluoromethyl-1H-pyrazoles (0.5 g, 3.7 mmol) using the generalprocedure A with a yield of 39% (0.35 g); MS (APCI) m/z: 243 (M+1, 100).

Step 2

4-(5-Trifluoromethyl-pyrazol-1-yl)phenol: The title compound wasprepared from 1-(4-methoxy-phenyl)-4-trifluoromethyl-1H-pyrazole (0.35g, 1.44 mmol) using the general procedure B with a yield of 67% (0.22g); MS (ESI) m/z: 227 (M-1, 100).

Step 3

1-{2-[4-(5-Trifluoromethyl-pyrazol-1-yl)-phenoxy]-ethyl}-piperidine 5d:The title compound was prepared from4-(5-trifluoromethyl-pyrazol-1-yl)phenol (0.1 g, 0.43 mmol),1-(2-chloroethyl)piperidine hydrochloride (0.16 g, 0.88 mmol) using thegeneral procedure C with a yield of 48% (70 mg); ¹H NMR (400 MHz, CDCl3)7.84 (d, J=2 Hz, 1H), 7.58 (d, J=9.2 Hz, 2H), 6.98 (d, J=9.2 Hz, 2H),6.65 (d, J=1.6 Hz, 1H), 4.14 (t, J=12, 6 Hz, 2H), 2.78 (t, J=12, 6 Hz,2H), 2.53 (br, 4H), 1.61-1.47 (m, 6H); LC/MS (ESI): 94%.

Example 5

Step 1

1-(4-Methoxy-phenyl)-3-methyl-5-trifluoromethyl-1H-pyrazole: The titlecompound was prepared from 4-methoxyphenylboronic acid (1.0 g, 6.7mmol), 5-trifluoromethyl-1H-pyrazoles (0.5 g, 3.33 mmol) using thegeneral procedure A with a yield of 41% (0.35 g); MS (APCI) m/z: 257(M+1, 100).

Step 2

4-(3-Methyl-5-trifluoromethyl-pyrazol-1-yl)-phenol: The title compoundwas prepared from1-(4-methoxy-phenyl)-3-methyl-5-trifluoromethyl-1H-pyrazole (0.35 g,1.37 mmol) using the general procedure B with a yield of 60% (0.2 g); MS(ESI) m/z: 243 (M+1, 100).

Step 3

1-{2-[4-(3-Methyl-5-trifluoromethyl-pyrazol-1-yl)-phenoxy]-ethyl}-piperidine:The title compound was prepared from4-(3-Methyl-5-trifluoromethyl-pyrazol-1-yl)-phenol (0.1 g, 0.42 mmol)and 1-(2-chloroethyl)piperidine hydrochloride (0.16 g, 0.88 mmol) usingthe general procedure C with a yield of 55% (80 mg); ¹H NMR (400 MHz,CDCl3) 7.33 (d, J=9.2 Hz, 2H), 6.98 (d, J=9.2 Hz, 2H), 6.43 (s, 1H),4.15 (t, J=12, 6 Hz, 2H), 2.78 (t, J=12, 6 Hz, 2H), 2.53 (br, 4H),1.61-1.47 (m, 6H); LC/MS (ESI): 94%.

Example 6

Step 1

4-[1,3]Dioxolan-2-yl-1-(4-methoxy-phenyl)-5-methyl-1H-pyrazole: Amixture of 1-(4-methoxy-phenyl)-5-methyl-1H-pyrazole-4-carbaldehyde (0.5g, 2.3 mmol), ethylene glycol (1.44 g, 23.1 mmol) and p-toluenesulfonicacid (0.2 g, 1.2 mmol) in toluene (10 mL) was refluxed for 18 h (DeanStock to remove water formed). After it was allowed to cool to roomtemperature, the reaction mixture was diluted with ethyl acetate, washedwith sat. NaHCO₃ (aq) and brine, and dried over Na₂SO₄. Afterconcentrated, the residue was purified by a column chromatography onsilica gel to yield the title compound (0.35 g, 58%); MS (APCI) m/z: 261(M+1, 80).

Step 2

1-(4-Hydroxy-phenyl)-5-methyl-1H-pyrazole-4-carbaldehyde: To a solutionof 4-[1,3]dioxolan-2-yl-1-(4-methoxy-phenyl)-5-methyl-1H-pyrazole (0.2g, 0.8 mmol) in CH₂Cl₂ (4 mL) was added boron tribromide (1M in DCM, 2.3mL, 2.3 mmol) at −78° C. over 5 min. The reaction mixture was stirred at−78° C. for 1 h, and then at room temperature for 4 h. The reaction wasquenched with sat. NaHCO₃ at 0° C., extracted with CH₂Cl₂, washed brine,and dried over Na₂SO₄. After concentrated in vacuo, the title compoundwas obtained with a yield of 97% (150 mg), which was used to the nextstep without further purifications; MS (APCI) m/z: 203 (M+1, 100).

Step 3

4-(4-Difluoromethyl-5-methyl-pyrazol-1-yl)-phenol: To a solution of1-(4-Hydroxy-phenyl)-5-methyl-1H-pyrazole-4-carbaldehyde (0.15 g, 0.74mmol) in methylene chloride (5 mL) was added DAST reagent (0.3 g, 1.26mmol) followed by ethanol (0.01 mL) at room temperature. The resultingreaction mixture was stirred at room temperature for 24 h. The reactionmixture was diluted with methylene chloride, washed with sat. NaHCO₃,water and brine, and dried over Na₂SO₄. After concentrated in vacuo, thetitle compound was obtained with a yield of 96% (160 mg), which was usedto the next step without further purifications.

Step 4

1-{2-[4-(4-Difluoromethyl-5-methyl-pyrazol-1-yl)-phenoxy]-ethyl}-piperidine:A mixture of 4-(4-Difluoromethyl-5-methyl-pyrazol-1-yl)-phenol (30 mg,0.134 mmol), 1-(2-chloroethyl)piperidine hydrochloride (50 mg, 0.27mmol), K₂CO₃ (55 mg, 0.4 mmol), in DMF (1 mL) was stirred at 90° C. for18 h. After the reaction mixture was quenched with water, the reactionmixture was extracted with CH₂Cl₂, washed 10% NaOH, and brine, driedover Na₂SO₄. After concentrated in vacuo, the residue was purified by acolumn chromatography on silica gel eluting with 20% ethylacetate/hexane to yield the title compound (25 mg, 56%); ¹H NMR (400MHz, CDCl3) 7.70 (br s, 1H), 7.30 (d, J=13.2 Hz, 1H), 7.00 (d, J=13.2Hz, 2H), 6.71 (t, J=96, 52 Hz, 1H), 4.16 (t, J=12, 6 Hz, 2H), 2.65 (t,J=12, 6 Hz, 2H), 2.53 (br, 4H), 2.34 (s, 3H), 1.61-1.47 (m, 6H); LC/MS(ESI) m/z: 336 (M+1, 100), 97%.

Example 7

Step 1

(R)-2-(4-Pyrrol-1-yl-phenoxymethyl)-pyrrolidine-1-carboxylic acidtert-butyl ester 1: To a 25 mL vial which contained a suspension of NaH(60% in mineral oil, 60 mg, 1.5 mmol) in DMF (5 mL) was added4-Pyrrol-1-yl-phenol (160 mg, 1 mmol) at 0° C. The mixture was allowedto warm to rt and stir at rt for 30 min then cooled to 0° C. To thisreaction mixture was added(R)-2-(toluene-4-sulfonyloxymethyl)-pyrrolidine-1-carboxylic acidtert-butyl ester (355 mg, 1 mmol) at 0° C. The resulting mixture wasallowed to warm to rt and stir at rt for 30 min and then was heated to90° C. and stirred at 90° C. for 16 h. After cooled to rt, the mixturewas poured into 150 mL ice-water solution and then was extracted withEtOAc (3×50 mL). The combined organic layers were washed with water(3×50 mL) and brine (30 mL), dried over Na₂SO₄. After concentrated invacuo, the residue was purified by a column chromatography on silica geleluting with ethyl ethyl acetate:hexane (1:10-1:4) to yield the titlecompound (270 mg, 80%); LCMS; m/z (ESI⁺ 243.3, M+1); 99%;

Step 2

1-[4-((R)-1-Pyrrolidin-2-ylmethoxy)-phenyl]-1H-pyrrole hydrochloride. Toa 20 mL vial which contained a solution of(R)-2-(4-Pyrrol-1-yl-phenoxymethyl)-pyrrolidine-1-carboxylic acidtert-butyl ester 1 (220 mg, 0.66 mmol) in dioxane (2 mL) was added HCl(4 N in dioxane, 2 mL) at 0° C. The mixture was allowed to warm to rtand stir at rt for 16 h. The solvent was removed and the crude waspurified by recrystallization from MeOH-ether to yield the desiredproduct (158 mg, 89%); ¹HNMR (400 MHz, CDCl3) 7.52 (d, J=9.2 Hz, 2H),7.27 (t, J=2.0 Hz, 2H), 7.07 (d, J=9.2 Hz, 2H), 6.23 (t, J=2.0 Hz, 2H),4.28 (dd, J1=10.4 Hz, J2=3.6 Hz, 1H), 4.12-4.17 (m, 1H), 3.86-3.96 (m,1H), 3.18-3.27 (m, 2H), 2.06-2.16 (m, 1H), 1.86-2.02 (m, 2H), 1.68-1.78(m, 1H); LCMS; m/z (ESI⁺ 243.5, M+1); 93%.

Example 8

1-[2-(4-Pyrrol-1-yl-phenoxy)-ethyl]-piperidine. To a 50 mL vial whichcontained a solution of 4-Pyrrol-1-yl-phenol (500 mg, 3.1 mmol) and1-(2-chloroethyl)piperidine hydrochloride (1.25 g, 6.2 mmol) in DMF (30mL) was added K₂CO₃ (1.8 g, 13 mmol) at rt. The reaction mixture washeated to 85° C. and stirred at 85° C. for 72 h. After cooled to rt, thereaction mixture was poured into 30 mL ice-water mixture and then wasextracted with EtOAc (3×50 mL). The combined organic layers were washedwith water (3×50 mL) and brine (30 mL), dried over Na₂SO₄. Afterconcentrated in vacuo, the residue was purified by a columnchromatography on silica gel eluting with ethyl acetate:hexane (1:4-1:1)to yield the title compound (330 mg 40%); ¹HNMR (500 MHz, CDCl3) 7.29(d, J=9.0 Hz, 2H), 6.99 (t, J=2.0 Hz, 2H), 6.95 (d, J=9.0 Hz, 2H), 6.32(t, J=2.0 Hz, 2H), 4.12 (t, J=6.0 Hz, 2H), 2.79 (t, J=6.0 Hz, 2H), 2.52(br, 4H), 1.44-1.63 (m, 6H); LCMS; m/z (ESI⁺ 271.6, M+1); 98%;

Example 9

1-{2-[4-(2-Bromo-pyrrol-1-yl)-phenoxy]-ethyl}-piperidine To a 50 mL vialwhich contained a solution of1-[2-(4-Pyrrol-1-yl-phenoxy)-ethyl]-piperidine (270 mg, 1 mmol) in THF(25 mL) was added NBS (250 mg, 1.4 mmol) at 0° C. The reaction mixturewas allowed to warm to rt and stir at rt for 48 h. The mixture waspoured into 30 mL ice-water mixture and then was extracted with EtOAc(3×30 mL). The combined organic layers were washed with water (3×30 mL)and brine (30 mL), dried over Na₂SO₄. After concentrated in vacuo, theresidue was purified by a column chromatography on silica gel elutingwith ethyl acetate:hexane (1:4-1:1) to afford the title compound (300 mg85%). ¹HNMR (400 MHz, CDCl3) 7.25 (d, J=9.0 Hz, 2H), 6.95 (d, J=9.2 Hz,2H), 6.84-6.85 (m, 1H), 6.28-6.29 (m, 1H), 6.24-6.26 (m, 1H), 4.14 (t,J=6.0 Hz, 2H), 2.80 (t, J=6.0 Hz, 2H), 2.52 (br, 4H), 1.42-1.65 (m, 6H);LCMS; m/z (ESI⁺ 351.1, M+2); 91%;

Example 10

1-[4-(2-Piperidin-1-yl-ethoxy)-phenyl]-1H-pyrrole-2-carbaldehyde To a 50mL vial which contained a solution of1-[2-(4-Pyrrol-1-yl-phenoxy)-ethyl]-piperidine (1.1 g, 4 mmol) and DMF(1 mL, 11 mmol) in toluene (15 mL) was added POCl₃ (1 mL, 4 mmol) at−78° C. The reaction mixture was allowed to warm to rt and then heatedto 85° C. and stirred at 85° C. for 16 h. After cooled to rt, thereaction mixture was poured into 100 mL ice-water mixture and then wasextracted with EtOAc (3×50 mL). The combined organic layers were washedwith water (3×50 mL) and brine (30 mL), dried over Na₂SO₄. Afterconcentrated in vacuo, the residue was purified by a columnchromatography on silica gel eluting with ethyl acetate:hexane (1:4-1:1)to provide the title compound (650 mg, 60%). ¹HNMR (400 MHz, CDCl3) 9.54(s, 1H), 7.25-7.27 (m, 2H), 7.14 (dd, J=4, 1.2 Hz, 1H), 7.02-7.03 (m,1H), 6.97 (d, J=8.8 Hz, 2H), 6.38 (dd, J=4, 1.2 Hz, 1H), 4.15 (t, J=6.4Hz, 2H), 2.81 (t, J=6.0 Hz, 2H), 2.53 (br, 4H), 1.42-1.65 (m, 6H); LCMS;m/z (ESI⁺ 299.4, M+1); 90%;

Compound Number

Example 1

Example 2

Example 3

Example 4

Example 5

Example 6

Example 7

Example 8

Example 9

Example 10

Assays to determine potency of LTA₄ hydrolase inhibitors:

(1) In vitro assay testing inhibitory activity against purifiedrecombinant human LTA₄ hydroase. A human LTA₄ hydrolase full-length cDNAclone (NM_(—)000895) was purchased from OriGene Technologies (Rockville,Md.). The gene was amplified by polmerase chain reaction and transferredvia pDONR201 into the bacterial expression vector pDEST17 byrecombination (both plasmids from Invitrogen, Carlsbad, Calif.). Theresulting construct was transformed into Escherichia coli BL21-AI(Invitrogen), and expression was induced by chemical induction witharabinose. The recombinant enzyme was purified by chromatography on anFPLC system (Amersham Biosciences, Uppsala, Sweden) using immobilizedmetal affinity chromatography (Ni-NTA Superflow, Qiagen, Hilden,Germany) and anion exchange chromatography (MonoQ HR 10/10, AmershamBiosciences).

The compounds of the invention were incubated in a series of dilutionswith 200 nM of recombinant enzyme in assay buffer (100 mM Tris-HCl, 100mM NaCl, 5 mg/ml fatty-acid free BSA, 10% DMSO, pH 8.0) for 10 min atroom temperature to allow binding between LTA₄ hydrolase and theinhibitors. LTA₄ was prepared by alkaline hydrolysis of LTA₄ methylester (Biomol, Plymouth Meeting, Pa., or Cayman Chemicals, Ann Arbor,Mich.). A solution of 10 μg of the ester was dried under a nitrogenstream and redissolved in 60 μl of a solution of 80% acetone and 20%0.25 M NaOH. After incubation for 40 min at room temperature theresulting approximately 500 μM tock of LTA₄ was kept at −80° C. for nomore than a few days prior to use.

Immediately before the assay, LTA₄ was diluted to a concentration of 10μM in assay buffer (without DMSO) and added to the reaction mixture to afinal concentration of 2 μM to initiate the enzyme reaction. Afterincubation for 120 sec at room temperature, the reaction was stopped byadding 2 volumes of chilled quenching buffer, containing acetonitrilwith 1% acetic acid and 225 nM LTB₄-d₄ (Biomol). The samples were thenkept at 4° C. overnight to complete protein precipitation andcentrifuged for 15 min at 1800 g. LTB₄ formed was measured by LC-MS/MSusing LTB₄-d₄ as an internal standard and an external LTB₄ standard(Biomol) as reference. Based on the amounts of LTB₄ found at eachinhibitor concentration, a dose-response curve was fitted to the dataand an IC₅₀ value was calculated.

(2) Ex vivo assay testing inhibitory activity in human whole blood afterstimulation with calcium ionophor.

Human blood was collected in heparin-containing Vacutainer tubes. Foreach sample, 200 μl of blood were dispensed into a pre-warmed plate and188 μl of RPMI-1640 medium (Invitrogen) containing 20 μg/ml indomethacin(Sigma, St. Louis, Mo.) were added. Then 4 μl of a series of compounddilutions (in DMSO) were added, followed by a 15 min incubation at 37°C. with gentle shaking. After that, blood samples were stimulated byadding lonomycin (Calbiochem) to a final concentration of 20 μM. Afteranother incubation at 37° C. for 30 min, samples were centrifuged for 5min at 1800 g and 4° C. Supernatants were taken and LTB₄ concentrationswere determined using a commercially available enzyme-linkedimmunosorbent assay (R&D Systems, Minneapolis, Minn.) according to themanufacturer's instructions. Results obtained for differentconcentrations of hydrolase inhibitor were then used to fit adose-response curve and calculate an IC₅₀ value.

The results of testing of representative species are shown below.

A = <5 μM, B = 5-20 μM, C = 20-30 μM Example # IC₅₀ (μM) 1 B 2 B 3 A 4 B5 A 6 B 7 A 8 A 9 A 10  A

We claim:
 1. A compound of formula:

wherein ring (a) is chosen from pyrazole and pyrrole unsubstituted orsubstituted with from one to three substituents independently selectedfrom the group consisting of halogen, hydroxyl, loweralkyl, loweracyl,loweralkoxy, fluoroloweralkyl, fluoroloweralkoxy, formyl, cyano, andnitro; Q is selected from the group consisting of a direct bond, O, S,SO, SO₂, NR¹, CH₂, CF₂, and C(O); n is 1 or 2; taken together ZW is H orZ is (CH₂)₁₋₁₀ in which one or two (CH₂) may optionally be replaced by—O—, —NR¹—, —SO—, —S(O)₂—, —C(═O)— or —C═O(NH)—; R¹ is chosen from H andlower alkyl; and W is selected from the group consisting of hydrogen,acyl, hydroxyl, carboxyl, amino, carboxamido, aminoacyl, —COOalkyl,—CHO, substituted aryl, sulfonamide, —C(O)fluoroalkyl,—C(O)CH₂C(O)Oalkyl, C(O)CH₂C(O)Ofluoroalkyl, —SH, —C(O)NH(OH),—C(O)N(OH)R⁴, —N(OH)C(O)OH, and —N(OH)C(O)R⁴; and R⁴ is selected fromthe group consisting of H and lower alkyl.
 2. A compound according toclaim 1, wherein Q is —O—.
 3. A compound according to claim 2, whereinring (a) is a pyrazole.
 4. A compound according to claim 3 of formula:

wherein R² is selected from the group consisting of H, halogen,hydroxyl, loweralkyl, loweracyl, loweralkoxy, fluoroloweralkyl,fluoroloweralkoxy, formyl, cyano, and nitro.
 5. A compound according toclaim 4, wherein ZW is hydrogen, or Z is (CH₂)₁₋₁₀; in which one or two(CH₂) may optionally be replaced by —O—, —NR¹—, —SO—, —S(O)₂—, —C(═O)—or —C═O(NH), and W is selected from the group consisting of acyl,hydroxy, carboxy, amino, carboxamido and aminoacyl.
 6. A compoundaccording to claim 5 of formula

wherein R² is chosen from H, loweralkyl, trifluoromethyl and halogen;and ZW is hydrogen or Z is chosen from (CH₂)₁₋₃ and —C(O)—, and W isselected from the group consisting of hydrogen, acyl, hydroxyl,carboxyl, amino, carboxamido, aminoacyl, COOloweralkyl and COOH.
 7. Acompound according to claim 2, wherein ring (a) is a pyrrole.
 8. Acompound according to claim 7 of formula:

wherein R³ is selected from the group consisting of H, halogen,loweralkyl, loweracyl, loweralkoxy, fluoroloweralkyl, fluoroloweralkoxy,formyl, cyano, and nitro.
 9. A compound according to claim 8, wherein ZWis hydrogen, or Z is (CH₂)₁₋₁₀; in which one or two (CH₂) may optionallybe replaced by —O—, —NR¹—, —SO—, —S(O)₂—, —C(═O)— or —C═O(NH), and W isselected from the group consisting of acyl, hydroxyl, carboxyl, amino,carboxamido and aminoacyl.
 10. A pharmaceutical composition comprising apharmaceutically acceptable carrier and a therapeutically effectiveamount of at least one compound according to claim 1.